Treatments in Parkinson’s disease

Treatment in PD

• Complex because of– Progressive nature of disease– Motor and non-motor features– Early and late side effects associated with the

treatments

Available Interventions

Goals of treatment in PD

• Prevention of disease progression• Symptomatic treatment of motor symptoms• Management of motor complications

– Wearing off/motor fluctuations– Dyskinesias

• Symptomatic treatment of non-motor symptoms

Prevention of disease progression

• “Neuroprotection is an unmet need in Parkinson’s disease and no drug can be recommended yet for this purpose in practice.”

Motor symptoms

• Symptoms that are being targeted by medications– Tremor– Rigidity– Bradykinesia– Gait/postural instability

Motor complications

• What are motor fluctuations/off time?• Periods of alteration of symptom control • On/off time – initially predictable, later unpredictable

• What are dyskinesias?• Drug-induced involuntary movements that include

chorea and dystonia

• Risk factors for development• Younger age at onset of PD, severity, higher L-dopa

dose and longer disease duration

Overview of topics

• Levodopa• Entocapone• Dopamine agonists• MAOB

inhibitors• Amantadine• Anticholinergics• Deep brain stimulation• Treatment of non-motor symptoms

Question

• The mechanism of the antiparkinsonian effect of rasagiline and selegiline is inhibition of: – A. aromatic amino acid decarboxylase– B. catechol-O-methyltransferase– C. monoamine oxidase type A– D. monoamine oxidase type B– E. tyrosine hydroxylase

Question

• True or false?• There is good evidence to support the use of

MAOB inhibitors as adjuncts to DA-agonists.• MAOB inhibitors effectively reduce dyskinesias

in patients with PD.

MAO INHIBITORS

Monoamine Oxidase (MAO)

• Group of enzymes involved in monoamine metabolism– Dopamine, serotonin, norepinephrine

• Two enzyme subtypes– Type A and type B

• In brain Both A+B• In GI tract mostly A

Substrates of MAOs

MAO Inhibitors (MAOI)

• Serendipitously discovered group of drugs with anti-depressant effect

• Despite effectiveness, second-line drug– “Cheese reaction” – Extensive side effect profile

What is the Cheese Reaction?

• Hypertensive crisis in patients on MAOIs who ingest tyramine

• Tyramine is a monoamine present in aged cheeses, red wine, sausages

• Usu. metabolised by MAO-A• Gut, portal circulation, peripheral neurons

• With MAOI (non-selective or selective for A) – Tyramine stimulates peripheral adrenergic neurons – Hypertensive crisis

Why use MAOIs in PD?

• MAO is present in brain, including the BG– Type B (80%) >> A

• If use selective MAO-B inhibitor:– Will inhibit dopamine metabolism in the BG (80%

type B)– Avoid cheese reaction (dependent on MAO-A)– Avoid extensive side effect profile

• Selective MAO-B inhibitors– Selegiline and rasagiline

Selegiline - Use

• What is the role of selegiline in the treatment of PD for relief of motor symptoms?

• AAN Practice Parameters (2002): – Can be used initially as monotherapy for mild

symptomatic relief• Movement Disorder Society (2002)

– Effective as monotherapy– Insufficient data to recommend use as as adjunct

in patients already on DA-ergic agents

Selegiline - Use

• What about its role in motor complications?– Insufficient data for fluctuations– Non-efficacious in preventing dyskinesias

• What about its role in neuroprotection?– Insufficient evidence to suggest that it has a

neuroprotective effect (despite initial studies)• Doses

– Start at 5mg daily– Increase to 5mg bid (maximum dose)

Selegiline – Side effects

• Mortality– One study showed excess mortality in selegiline

group– Meta-analysis did not confirm this

• Headache, nausea, insomnia• Confusion in the elderly• Can enhance side effects of L-dopa

– (But no evidence to use together)

Rasagiline (Azilect)

• What is the role for rasagiline in mgmnt of motor symptoms?

• Movement Disorder Society (2005)– Effective as monotherapy– Insufficient data to recommend use as adjunct in

patients already on DA-ergic agents– Insufficient data regarding role in motor

complications (MDS)

Rasagiline (Azilect)

• Doses– Start at 0.5mg daily– Increase to 1mg daily (maximum dose)

• Side effects– Same as selegiline

OTHER

Question

• In which group of PD patients would you consider using anticholinergics? – A. Younger patients with predominant rigidity– B. Younger patients with predominant tremor– C. Elderly patients with predominant motor

fluctuations– D. Elderly patients with predominant non-motor

symptoms

Anticholinergics

• Mechanism of Action in PD– Not clearly known– Degeneration of DA-ergic nigrostriatal neurons

imbalance between striatal dopamine and Ach – Anticholinergics help counteract the imbalance

Anticholinergics - Use

• What is the role for anticholinergics in the management of PD?

• 1993 AAN Practice parameters– Can be considered as initial therapy esp. if tremor

predominant• MDS (2002)

– Likely efficacious as monotherapy in early PD and as adjunct in patients on L-dopa

– Insufficient data re: efficacy for prevention/treatment of motor fluctuations

• Typically: young patients with predominant tremor

Anticholinergics – Side effects

• Main ones (start low, go slow):– Trihexyphenidyl (Artane)

• Start 0.5-1mg bid, increase to 2mg tid

– Benztropine (Cogentin)• Start 0.5-1 mg bid, increase to 2 bid

• Side effects– Confusion, hallucinations, blurry vision, increased

intraocular pressure, dry mouth, urinary retention, constipation

Amantadine

• Used in PD for over 40 years• Antiparkinsonian MoA not fully known

– Partial NMDA receptor antagonist– Partial dopamine agonist

Amantadine - Use

• What is the role for amantadine in the treatment of motor symptoms?– Safe and modestly effective (AAN)– “Likely efficacious” as monotherapy in early PD (MDS)

• What about its role in motor complications?– “Possibly efficacious” at reducing dyskinesias– May be considered for pts with motor fluctuations– Efficacious in pts on L-Dopa with motor complications

Amantadine - Use

• Role in motor complications ctn’d– Effect on dyskinesias likely better than more frequent dosing

of L-Dopa– Unknown efficacy in comparison to DA-agonist (pramipexole,

ropinirole)• Dose

– 100 mg po daily to qid• Side effects

– Livedo reticularis, leg edema, – Same side effect profile as dopamine agonists– Generally well-tolerated

NON-MOTOR SYMPTOMS

• A 78-year-old woman with a 15-year history of PD has developed visual hallucinations. Her medications include carbidopa/levodopa, ropinirole, and rasagiline. Her hallucinations have not diminished significantly with trials of reductions of each of her medications. Which of the following medications is most appropriate for this patient?– A. chlorpromazine– B. haloperidol– C. quetiapine– D. thioridazine– E. thiothixene

Non-motor symptoms

• “Non-motor symptoms dominate the clinical picture of advanced Parkinson’s disease and contribute to severe disability, impaired quality of life, and shortened life expectancy”

Pathophysiology

• Non-dopaminergic-cell dysfunction thought to play a major part in the development of the non-motor symptoms

• However, neuroanatomy and neurochemistry of non-motor symptoms are unknown

Non-motor symptoms• Neuropsychiatric symptoms

– Depression, apathy, anxiety, hallucinations, dementia, impulsive behavior (usu drug-induced)

• Sleep disorders– Restless legs and period limb movements, REM-sleep behavior disorder,

excessive daytime somnolence• Autonomic symptoms

– Bladder (urgency, nocturia, frequency), sweating, orthostatic hypotension, sexual dysfunction

• GI symptoms (overlap with dysautonomia)– Dribbling saliva, constipation, dysphagia, ageusia,

• Sensory symptoms– Olfactory disturbance, pain, paresthesias

Management

• Depression• Anxiety• Psychosis• Orthostatic hypotension• Dementia• Sexual dysfunction• Sleep dysfunction

Management - Depression

• Can affect from 10-45% of patients• Likely has a biological contribution

– May be a result of impaired 5HT transmission• What is best pharmacological treatment? (AAN 2006)

– The highest level of evidence is for amitriptyline– Although it may be considered, it is not necessarily the first

choice for treatment of depression associated with PD. – Insufficient evidence to make recommendations regarding

other treatments for depression• SSRIs and SNRIs are used but little published data in PD

Management – Anxiety and Apathy

• Anxiety disorder common– Often coexists with depression– Panic attacks, phobias, GAD, related to motor

fluctuations• AAN practice parameters regarding treatment

– Insufficient evidence to make any recommendations

Management - Psychosis

• What is the best treatment for patients with PD and psychosis?– Clozapine should be considered

• Remember: associated with agranulocytosis that may be fatal. The absolute neutrophil count must be monitored.

– Quetiapine may be considered– Olanzapine should not be routinely considered

• No proven efficacy and may worsen motor function

• Note that not FDA approved because of increased risk of death in pts with dementia

Management - Dementia

• What are the most accurate screening tools in PD?– MMSE and CAMCog (Cambridge cognitive assessment)– MMSE as sensitive but not as specific

• What is the most effective treatment for dementia in PD?– Rivastigmine probably effective in improving cognitive

function. Modest effect and may exacerbate tremor– Donepezil is probably effective in improving cognitive

function. Modest effect.

Management – Orthostatic Hypotension

• Defined as a 20mmHg drop in systolic BP or a 10mmHg drop in diastolic BP

• Challenge in PD – DA-ergic agents often worsen OH – Reducing dose usually insufficient to treat

• What treatments are effective? (AAN 2006)– Insufficient data to recommend to any particular

treatment

Management – Orthostatic Hypotension

• Compression stockings• Increasing water intake• Fludrocortisone

• Dose: 0.1 – 0.3mg daily + high Na intake• Supine hypertension, peripheral edema

• Midodrine • Peripheral alpha1 receptor agonist• Dose: 2.5 to 5mg tid

• Others: domperidone, pyridostigmine, indomethacin

Management – Sexual Dysfunction

• Common in both men and women • Multifactorial

– Motor dysfunction, medication side effects, mood disorders, and dysautonomia

– Dysautonomia erectile dysfunction • One study looked at sildenafil in ED

– 12 patients with PD, BP > 90/50– Sildenafil at 50mg significantly improved ED

Management – Sexual Dysfunction

• AAN Practice Parameter– Sildenafil possibly efficacious

• Need to ensure that other treatable causes of ED/sexual dysfctn have also been addressed

• Note: hypersexuality can be seen in PD associated with DA-ergic agents

• A 48-year-old man with a 1-year history of PD comes to the office with his wife. She states that for the past 5 years he’s had episodes of kicking and punching during sleep. This has resulted in injuries to both. He is currently taking no medications.

• What is the diagnosis?• Which of the following is most likely to benefit this

patient’s nocturnal symptoms?– A. amantadine– B. clonazepam– C. pramipexole– D. ropinirole– E. selegiline

Management – Sleep Dysfunction

• Range of sleep dysfunction– REM sleep behavior disorder (RBD)– Excessive daytime somnolence (EDS)– Insomnia– Restless legs syndrome and periodic limb

movement

Management – RBD

• A type of parasomnia characterized by patients acting out dramatic or violent dreams during the REM sleep stage.

• What treatments are effective in PD? – Insufficient data

• What treatments are available for RBD? – Clonazepam - 0.25 to 1mg po qhs– Melatonin

Question

Management - EDS

• May be 2ary to disease process or medication side effect

• Dopaminergic agents can cause mild to severe somnolence– Falling asleep at wheel of car– Agonists > L-dopa– FDA warnings for pramipexole and ropinirole– Patients should be advised to d/c DA agonists if

marked increase in sleepiness

Management - EDS

• What treatments are available?– Modafinil improves SUBJECTIVE feeling of

sleepiness but doesn’t change OBJECTIVE measurements of somnolence

– Dose: 200mg daily in am

Management - Insomnia

• Etiology is multifactorial – Mood disturbances, persistent tremor, nighttime PD

symptoms, nocturia, and reversal of sleep patterns• Practice parameter: Insufficient data• Available treatments

– Bedtime L-dopa – may improve nocturnal PD sx– Melatonin – Improves perception– Sedating antidepressants (trazodone)– Mild sedatives – zopiclone, zolpidem– Over-the-counter sleeping aids – beware of side effects

(anticholinergic effect)

Management - RLS

• Occurs in up to 20% of patients• No evidence on how to treat of RLS in PD• May use ropinirole and pramipexole

– FDA approved treatment in primary RLS

Summary

• MAOB Inhibitors– Monotherapy, early PD– Not for motor complications or neuroprotection

• Anticholinergics– Young patients with predominant tremor– Not for motor complications

• Amantadine– Monotherapy for motor symptoms– Adjunct if L-dopa induced motor complications

Summary

• Depression– Consider amitryptilline

• Psychosis– Clozapine > quetiapine

• Dementia– Rivastigmine and donepezil

• Orthostatic hypotension– Non-pharm; fludro, midodrine, domperidone

Summary

• RBD– Clonazepam

• EDS– Warn patients!– Remove offending agent

• RLS– Pramipexole and ropinirole

CASES

Case 1

• 44 y.o. woman. New left hand tremor and shoulder stiffness. Not yet interfering with work.

• On exam – left sided rigidity, bradykinesia and tremor

• Assuming that your best diagnosis is IPD:– Should you start the patient on treatment?– What treatment would you start? What are the

benefits/disadvantages of the different options?

Case 1

• Should you start the patient on treatment?– No evidence that starting treatment early is

harmful or worsens long-term outcome– Therefore, generally decision to start treatment

should take into account degree of symptoms/disability versus adverse effects of medication

Case 1

• What treatment would you start? What are the benefits/disadvantages of the different options?– Levodopa –less sleepiness and psych Ses, but higher

rate of dyskinesias– Dopamine agonists – longer duration of action, less

dyskinesias, but greater sleepiness and psychiatric SEs

– MAOB inhibitors– Anticholinergics– Amantadine

Case 2

• 65 y.o. man, PD x 5 yrs• On Sinemet 100/25 qid and selegiline 5 bid• For 1 yr: am off time before meds kick in and

pm dyskinesias

• How can you decrease morning off time?• How can you decrease dyskinesias?

Case 2

• How can you decrease morning off time?– Adding a COMT inhibitor however, can increase

dyskinesias– Adding pramipexole or ropinirole may increase

dyskinesias– Adding amantadine (less evidence for motor

fluctuations)• How can you decrease dyskinesias?

– Adding DA- agonist and reducing L-Dopa dose slowly– Adding Amantadine

Case 3

• 73 y.o. woman, PD x 10 years• On Sinemet and pramipexole

– Mild dyskinesias and motor fluctuation• Recent forgetfulness and apparent visual

hallucinations. • On exam, MMSE 27/30 and mild choreatic

dyskinesias

Case 3

• What single intervention is most likely to reduce hallucinations?

• If that fails to control hallucinations, what is the next step?

• Would you treat her mild cognitive impairment?

Case 3

• What single intervention is most likely to reduce hallucinations?– Remove the pramipexole– This may lead to increased motor fluctuations and

dyskinesias and require Sinemet dose adjustment• If that fails to control hallucinations, what is

the next step?– Atypical antipsychotics: clozapine, quetiapine

Thank you

Review Question

• A 51 y.o. woman developed PD and was started on treatment. Soon after, she began to spend money on frivolous items and went to the casino where she lost her life savings.

• What is the diagnosis?• It is a side effect of which class of medication?

– MAOB inhibitors– Dopamine agonists– Anticholinergics – COMT inhibitors

Review Question

• Which of the following agents can be used as monotherapy in PD (choose as many as apply)– Pramipexole– Ropinirole– Rasagiline and selegiline– Benztropine and trihexyphenidyl– Amantadine

Figure 1. The mechanism of potentiation of cardiovascular effects of tyramine, the cheese reaction, and NE release and metabolism after MAO-A inhibition.

Youdim M B , Riederer P F Neurology 2004;63:S32-S35

©2004 by Lippincott Williams & Wilkins

• Mechanism of action of MAOI (no pdf)– http://www.neurology.org/content/63/7_suppl_2

/S32.full• Treatment interventions in PD: and evidence

based assessment. Rascol et al. Lancet 2002;359:1589.

• Evidence-based medical review update: Pharmacological and surgical treatments of PD: 2001-2004. Movement Disorders 2005;20(5):523

• Goetz CG, Koller WC, Poewe W, et al. Management of Parkinson’s disease: an evidence-based review. Mov Disord 2002;17(Suppl. 4)S1–S166.

• Update on the medical management of parkinson disease. Continuum 2010;16:96-109

• Chaudhuri et al. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006;5:235-45.

Figure 2. The pathway of dopamine (DA) synthesis from levodopa (l-dopa) and its metabolism by intraneuronal MAO-A and by MAO-A and B extraneuronally by glia and astrocytes and the

inhibition of MAO by various selective (moclobemide, selegiline, rasagiline) ...

Youdim M B , Riederer P F Neurology 2004;63:S32-S35

©2004 by Lippincott Williams & Wilkins

• Which of the following sleep disorders is most common in patients with Parkinson disease?

• A. central sleep apnea• B. delayed sleep phase syndrome• C. narcolepsy• D. REM sleep behavior disorder